Anesthesia triggers drug delivery to experimental glioma in mice by hijacking caveolar transport

Abstract Background: Pharmaceutical intervention in the CNS is hampered by the shielding function of the blood-brain barrier (BBB). To induce clinical anesthesia, general anesthetics such as isoflurane readily penetrate the BBB. Here, we investigated whether isoflurane can be utilized for therapeutic drug delivery. Methods: Barrier function in primary endothelial cells was evaluated by transepithelial/transendothelial electrical resistance, and nanoscale STED and SRRF microscopy. In mice, BBB permeability was quantified by extravasation of several fluorescent tracers. Mouse models including the GL261 glioma model were evaluated by MRI, immunohistochemistry, electron microscopy, western blot, and expression analysis. Results: Isoflurane enhances BBB permeability in a time- and concentration-dependent manner. We demonstrate that, mechanistically, isoflurane disturbs the organization of membrane lipid nanodomains and triggers caveolar transport in brain endothelial cells. BBB tightness re-establishes directly after termination of anesthesia, providing a defined window for drug delivery. In a therapeutic glioblastoma trial in mice, simultaneous exposure to isoflurane and cytotoxic agent improves efficacy of chemotherapy. Conclusions: Combination therapy, involving isoflurane-mediated BBB permeation with drug administration has far-reaching therapeutic implications for CNS malignancies

Search for CP Violation in the Decay Z -> b (b bar) g

About three million hadronic decays of the Z collected by ALEPH in the years 1991-1994 are used to search for anomalous CP violation beyond the Standard Model in the decay Z -> b \bar{b} g. The study is performed by analyzing angular correlations between the two quarks and the gluon in three-jet events and by measuring the differential two-jet rate. No signal of CP violation is found. For the combinations of anomalous CP violating couplings, ${\hat{h}}_b = {\hat{h}}_{Ab}g_{Vb}-{\hat{h}}_{Vb}g_{Ab}$ and $h^{\ast}_b = \sqrt{\hat{h}_{Vb}^{2}+\hat{h}_{Ab}^{2}}$, limits of \hat{h}_b < 0.59$and$h^{\ast}_{b} < 3.02$ are given at 95\% CL.Comment: 8 pages, 1 postscript figure, uses here.sty, epsfig.st

A Conserved CXXC Motif in CD3ε Is Critical for T Cell Development and TCR Signaling

Structural integrity of the extracellular membrane-proximal stalk region of CD3ε is required for efficient signaling by the T cell antigen receptor complex. The results in this article suggest that receptor aggregation may not be sufficient for a complete T cell receptor signal and that some type of direct allosteric signal may be involved

Synthetic Nanoparticles for Vaccines and Immunotherapy

The immune system plays a critical role in our health. No other component of human physiology plays a decisive role in as diverse an array of maladies, from deadly diseases with which we are all familiar to equally terrible esoteric conditions: HIV, malaria, pneumococcal and influenza infections; cancer; atherosclerosis; autoimmune diseases such as lupus, diabetes, and multiple sclerosis. The importance of understanding the function of the immune system and learning how to modulate immunity to protect against or treat disease thus cannot be overstated. Fortunately, we are entering an exciting era where the science of immunology is defining pathways for the rational manipulation of the immune system at the cellular and molecular level, and this understanding is leading to dramatic advances in the clinic that are transforming the future of medicine.1,2 These initial advances are being made primarily through biologic drugs– recombinant proteins (especially antibodies) or patient-derived cell therapies– but exciting data from preclinical studies suggest that a marriage of approaches based in biotechnology with the materials science and chemistry of nanomaterials, especially nanoparticles, could enable more effective and safer immune engineering strategies. This review will examine these nanoparticle-based strategies to immune modulation in detail, and discuss the promise and outstanding challenges facing the field of immune engineering from a chemical biology/materials engineering perspectiveNational Institutes of Health (U.S.) (Grants AI111860, CA174795, CA172164, AI091693, and AI095109)United States. Department of Defense (W911NF-13-D-0001 and Awards W911NF-07-D-0004

BCR-signalling synergizes with TLR-signalling for induction of AID and immunoglobulin class-switching through the non-canonical NF-κB pathway

By diversifying antibody biological effector functions, class switch DNA recombination has a central role in the maturation of the antibody response. Here we show that BCR-signalling synergizes with Toll-like receptor (TLR) signalling to induce class switch DNA recombination. BCR-signalling activates the non-canonical NF-κB pathway and enhances the TLR-dependent canonical NF-κB pathway, thereby inducing activation-induced cytidine deaminase (AID), which is critical for class switch DNA recombination. Escherichia coli lipopolysaccharide (LPS) triggers dual TLR4/BCR-signalling and induces hallmarks of BCR-signalling, including CD79a phosphorylation and Ca2+ mobilization, and activates both the NF-κB pathways to induce AID and class switch DNA recombination in a PI(3)K p85α-dependent fashion. CD40-signalling activates the two NF-κB pathways to induce AID and class switch DNA recombination independent of BCR-signalling. Finally, dual BCR/TLR-engaging NP–lipopolysaccharide effectively elicits class-switched NP-specific IgG3 and IgG2b in mice. Thus, by integrating signals of the non-canonical and canonical NF-κB pathways, BCR and TLRs synergize to induce AID and T-cell-independent class switch DNA recombination

Production of excited beauty states in Z decays

A data sample of about 3.0 million hadronic Z decays collected by the ALEPH experiment at LEP in the years 1991 through 1994, is used to make an inclusive selection of B~hadron events. In this event sample 4227 \pm 140 \pm 252 B^* mesons in the decay B^* \to B \gamma and 1944 \pm 108 \pm 161 B^{**} mesons decaying into a B~meson and a charged pion are reconstructed. For the well established B^* meson the following quantities areobtained: \Delta M = M_{B^*} - M_{B} = (45.30\pm 0.35\pm 0.87)~\mathrm{MeV}/c^2 and N_{B^*}/(N_B+N_{B^*}) = (77.1 \pm 2.6 \pm 7.0)\%. The angular distribution of the photons in the B^* rest frame is used to measure the relative contribution of longitudinal B^* polarization states to be \sigma_L/(\sigma_L + \sigma_T)= (33 \pm 6 \pm 5)\%. \\ Resonance structure in the M(B\pi)-M(B) mass difference is observed at (424 \pm 4 \pm 10)~\mathrm{MeV}/c^2. Its shape and position is in agreement with the expectation for B^{**}_{u,d} states decaying into B_{u,d}^{(*)} \pi^\pm. The signal is therefore interpreted as arising from them. The relative production rate is determined to be \frac{BR(Z \to b \to B_{u,d}^{**})}{BR(Z \to b \to B_{u,d})} = [27.9 \pm 1.6(stat) \pm 5.9(syst) \phantom{a}^{+3.9}_{-5.6}(model)]\%. where the third error reflects the uncertainty due to different production and decay models for the broad B_{u,d}^{**} states

Tau hadronic branching ratios

From 64492 selected \tau-pair events, produced at the Z^0 resonance, the measurement of the tau decays into hadrons from a global analysis using 1991, 1992 and 1993 ALEPH data is presented. Special emphasis is given to the reconstruction of photons and \pi^0's, and the removal of fake photons. A detailed study of the systematics entering the \pi^0 reconstruction is also given. A complete and consistent set of tau hadronic branching ratios is presented for 18 exclusive modes. Most measurements are more precise than the present world average. The new level of precision reached allows a stringent test of \tau-\mu universality in hadronic decays, g_\tau/g_\mu \ = \ 1.0013 \ \pm \ 0.0095, and the first measurement of the vector and axial-vector contributions to the non-strange hadronic \tau decay width: R_{\tau ,V} \ = \ 1.788 \ \pm \ 0.025 and R_{\tau ,A} \ = \ 1.694 \ \pm \ 0.027. The ratio (R_{\tau ,V} - R_{\tau ,A}) / (R_{\tau ,V} + R_{\tau ,A}), equal to (2.7 \pm 1.3) \ \%, is a measure of the importance of QCD non-perturbative contributions to the hadronic \tau decay widt